Piperazine, piperidine and 1,2,5,6-tetrahydropyridine

ABSTRACT

A compound selected from those of formula: ##STR1## wherein: A-B, n, D and E are as defined in the specification, 
     their racemic mixtures, and their optical isomers, 
     and also the physiologically tolerable salts thereof with appropriate acids. 
     The products of the invention may be used therapeutically.

The present application is a division of our prior-filed copendingapplication Ser. No. 08/655,457, filed May 30, 1996, now pending.

The present invention relates to new piperazine, piperidine and1,2,5,6-tetrahydropyridine compounds.

It relates more especially to compounds of formula I: ##STR2## wherein

A-B is selected from the group consisting of: CH₂ --CH, CH═C and CH₂--N,

n is selected from the group consisiting of zero and integers of from 1to 6 inclusive,

D represents one of the following bicyclic systems: ##STR3## wherein:

R₁ and R₂, which are identical or different, are each selected from thegroup consisting of hydrogen and halogen atoms, straight-chain andbranched alkyl and alkoxy radicals each having from 1 to 5 carbon atomsinclusive and a hydroxy radical; and

E represents one of the following heterocycles: ##STR4## but with theproviso that E does not represent: ##STR5## when D is selected from thegroup consisting of ##STR6##

The presence of asymmetric carbon atoms implies that the molecules ofthe invention exist in the form of a racemic mixture or racemate andoptical isomers or enantiomers, which are also included in the presentinvention. Furthermore, the compounds of the invention may form, withpharmaceutically acceptable acids, mineral or organic acid salts towhich the present invention also relates.

The dopaminergic system is implicated in a significant number ofdisorders of the central nervous system that are associated either witha hyperactivity (such as, for example, schizophrenia) or with ahypoactivity (such as, for example, Parkinson's disease) of that system.Depression, impulse disorders and memory disorders also belong to theillnesses for which it has been possible to demonstrate the part playedby dopamine in their etiology. Until now, treatment of those illnesseshas been ensured by D₂ dopaminergic blockers (for disorders associatedwith hyperactivity) and by D₂ dopaminergic activators (for disordersassociated with hypoactivity). However, treatments with conventionalneuroleptics, which are D₂ dopaminergic receptor blockers, have numerousside effects: tardive dyskinesia, malignant neuroleptic syndrome,hyperprolactinaemia and amenorrhoea. In addition, D₂ dopaminergicreceptor stimulants cause nausea and troublesome motor andcardiovascular side effects. Recently, three other dopaminergicreceptors have been discovered in addition to the already known D₁ andD₂ receptors: D₃ (P. Sokoloff et al, Nature, 1990, 347, 147), D₄ (VanTol et al, Nature, 1991, 350, 610) and D₅ (Sunhara et al, Nature, 1991,350, 614). The present invention relates more especially to D₄ receptoragonist or antagonist ligands that possess a high selectivity inrelation to other dopaminergic receptors, especially D₂ receptors,giving those products valuable therapeutic properties because of therelative absence of D₄ receptor in the hypophysis and in the basalganglia structures and without, at the same time, the known side effectsof D₂ ligands.

It should also be mentioned that an increase of cortical dopaminergictransmission plays a key role in the treatment of the deficient symptomsof schizophrenia.

The closest prior art to the present invention relates to1-(2,3-dihydro-1,4-benzodioxin-6-yl)-piperazine compounds, described inthe patent specifications U.S. Pat. No. 5,242,925 (serotoninagonists/antagonists), EP 0 300 908 (anti-arrhythmics), EP 0 072 960 andEP 0 072 961 (anti-allergics). Those patent specifications nowhereeither include or suggest the compounds forming the object of thepresent invention and could not influence the patentability of thepresent Application.

The compounds of the present invention thus differ from the compounds ofthe prior art not only in their chemical structure but also in respectof their pharmacological and therapeutic activities. Those activitieshave been demonstrated:

in vitro

by cloned human D₂ and D₄ receptor binding studies

and

in vivo

a) using pharmacological models:

by dopamine synthesis (turnover) studies in the following structures:frontal cortex (mesocortical pathway), nucleus accumbens and olfactorytubercle (mesolimbic pathway), striatum (nigrostriatal pathway). Thefunctional dopaminergic antagonists cause an increase in the synthesisof dopamine in those structures.

by dialysis studies in the structures mentioned above, during the courseof which the products of the invention are characterised as a functionof their effects on dopaminergic, noradrenergic or seretoninergicactivity. A selective increase in the release of dopamine in the frontalcortex compared with the nucleus accumbens and the striatum makes itpossible to forecast therapeutic effects of an antidepressant,antipsychotic and pro-mnesic type.

The above activities have been confirmed.

b) using therapeutic models:

and especially using the following tests:

the inhibition of verticalisation induced by apomorphine in mice(antipsychotic properties)

the inhibition of aggressiveness in isolated mice (anti-impulse andanxiolytic properties).

On the other hand, the absence of side effects has been demonstratedespecially by an absence of activity in

the catalepsy induction test in the rat.

Thus, in their activity as selective ligands of D₄ receptors, theproducts of the invention may be used in the prevention of, or indisorders associated with, a dysfunction of the dopaminergic system.More especially, their usefulness as antipsychotics and anti-depressantsin the treatment of impulse disorders and memory disorders, and asanxiolytics, is claimed in relation to their activity in the testsmentioned above.

The invention relates also to a process for the preparation of compoundsof formula I which is characterised in that:

a compound of formula II: ##STR7## wherein A-B and E are as definedabove, is condensed with a compound of formula III:

    D--(CH.sub.2)n--X                                          (III)

wherein n and D are as defined above and X represents a halogen atom ora mesyloxy or tosyloxy radical.

The condensation is carried out especially suitably in an appropriatesolvent, such as, for example, methyl ethyl ketone, methyl isobutylketone, toluene, dimethylformamide or dimethyl acetamide, in thepresence of an acceptor for the acid formed during the course of thereaction, at a temperature of from 20° to 150° C. There may be used asacceptor, for example, an alkali metal carbonate, such as sodiumcarbonate, or a tertiary amine, such as triethylamine.

Furthermore, compounds of formula I wherein n has a meaning other thanzero, that is to say compounds corresponding more precisely to formulaI': ##STR8## wherein A-B, D and E are as defined above and n' representsan integer of from 1 to 6, have also been prepared in accordance with avariant of the above process which is characterised in that:

a compound of formula II defined above

is condensed with

a compound of formula IV:

    D--(CH.sub.2).sub.n'-1 --CO.sub.2 H                        (IV)

wherein:

D and n' are as defined above,

and the amide so obtained of formula V: ##STR9## wherein

A-B, D, E and n' are as defined above, is reduced.

The condensation of compounds II and IV is especially suitably carriedout in an appropriate solvent, such as, for example, methylene chloride,in the presence of carbonyldiimidazole.

The reduction of amide V is advantageously carried out by means of alithium aluminium hydride in ether or tetrahydrofuran or by means ofborane-dimethyl sulphide in tetrahydrofuran, or sodiumalkoxyaluminohydride in toluene such as Red Al®.

The latter process for the preparation of compounds I' is also includedin the present invention.

In addition, the amides of formula V are new intermediate productswhich, as such, form part of the present invention.

The starting materials of formulae II, III and IV are either knownproducts, or products prepared from known compounds in accordance withknown processes, as specified in the Examples hereinafter.

The compounds of formula I yield salts with physiologically tolerableacids. Those salts are also included in the present invention.

The present invention relates also to pharmaceutical compositionscomprising as active ingredient a compound of the general formula I or aphysiologically tolerable salt thereof, mixed with or in associationwith an appropriate pharmaceutical excipient, such as, for example,glucose, lactose, talc, ethyl cellulose, magnesium stearate or cocoabutter. The pharmaceutical compositions so obtained are generallypresented in dosage form and may contain from 0.1 to 100 mg of activeingredient. They may, for example, be in the form of tablets, dragees,gelatin capsules, injectable or drinkable solutions and, depending onthe case in question, may be administered by the oral, rectal orparenteral route at a dose of from 0.1 to 100 mg of active ingredientfrom 1 to 3 times per day.

The following Examples illustrate the present invention, melting pointsbeing determined with a Kofler hot plate (K), where required undermicroscope (M.K.).

EXAMPLE 11-(Benzocyclobutan-1-ylmethyl)-4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine##STR10##

2.26 g (7.8×10-3 mol) of 1-hydroxymethylbenzocyclobutane tosylate, 1.7 g(7.8×10-3 mol) of 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine and2.16 g (15.6×10-3 mol) of K2CO3 in 50 ml of methyl isobutyl ketone aremixed together. That mixture is heated at 100° C. for 8 hours and thencooled. The mixture is concentrated and the residue is taken up in waterand ethyl acetate. Separation is carried out and the organic phase thenextracted with 1N HCl. The aqueous phase is rendered basic with 1N NaOHand then extracted with methylene chloride and dried over MgSO4. The oilobtained is purified by flash chromatography (eluant CH2Cl2/CH3OH:95/5). 1 g (yield=38%) of an oil that corresponds to the title compoundis obtained, the dihydrochloride of which is prepared in acetonitrile.M.p. 242°-245° C.

EXAMPLE 2 4-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-1-(indan-2-yl)piperazine##STR11##

Prepared in the same manner as in Example 1, but using indan-2-oltosylate instead of 1-hydroxymethylbenzocyclobutane tosylate, the titlecompound obtained melts at 183°-185° C.

EXAMPLE 3 1-2-(Benzocyclobutan-1-yl)ethyl!-4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine##STR12##

2.21 g (8.2 mmol) of 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine(Preparation 1), 1.72 g (8.2 mmol) of2-(benzocyclobutan-1-yl)-1-bromoethane and 3.48 g (32.8 mmol) of sodiumcarbonate in 33 ml of methyl isobutyl ketone are heated at reflux for 14h. The whole is evaporated to dryness, taken up in 200 ml of ethylacetate and 100 ml of N sodium hydroxide solution and decanted, and theorganic phase is washed with 100 ml of a saturated sodium chloridesolution. After drying over MgSO₄ and evaporation, the residue obtainedis chromatographed on silica (eluant: CH₂ Cl₂ /CH₃ OH: 98/2) to yield2.1 g of the expected product. By the addition of a 2% fumaric acidsolution in ethanol, 1.7 g of the fumarate of the title compound isobtained. M.p. 193°-194° C.

EXAMPLE 4 1-(2,3-Dihydro-5-methoxybenzofuran-6-yl)-4-2-(naphth-1-yl)ethyl!piperazine ##STR13##

Prepared in the same manner as the product of Example 3 but using2-(naphth-1-yl)-1-bromoethane instead of2-(benzocyclobutan-1-yl)-1-bromoethane.

The resulting fumarate of the title compound melts at 177°-179° C. afterrecrystallisation from ethanol.

EXAMPLE 5 4-2-(Benzocycloheptan-1-yl)ethyl!-1-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine##STR14##

Prepared in the same manner as the product of Example 3 but using2-(benzocycloheptan-1-yl)ethanol mesylate instead of2-(benzocyclobutan-1-yl)-1-bromoethane.

The resulting fumarate of the title compound melts at 225°-227° C. afterrecrystallisation from ethanol.

EXAMPLE 64-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-1-(indan-2-ylmethyl)piperazine##STR15## Step 1. "Amide"

Add 4.9 g (29.5 mmol) of carbonyldiimidazole in one go to 4.9 g (29.5mmol) of indan-2-ylcarboxylic acid dissolved in 50 ml of methylenechloride. The reactants are left in contact for one hour after theevolution of gas has ceased, then 6.4 g (29.5 mmol) of4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine dissolved in 50 ml ofmethylene chloride is rapidly added dropwise. The reactants are left incontact overnight, transferred to a separating funnel and extracted with1N HCl. The acidic phases are rendered basic cold and extracted withethyl acetate. 8.3 g of the expected amide (yield=69%) are obtained,which are used without being purified.

Step 2. Title compound

A solution of 8 g (21.9 mmol) of the amide obtained above in 100 ml ofTHF is poured into 0.8 g of LiAlH₄ suspended in 30 ml of THF. Thereactants are left in contact overnight and the mixture is decomposed insuccession with H₂ O (0.54 ml), 20% NaOH (0.44 ml) and H₂ O (2 ml). Theprecipitate is filtered, washed with THF and evaporated to obtain an oilthat corresponds to the desired product. By means of the slow additionof an ethereal hydrogen chloride solution to the base dissolved inacetonitrile, 1.5 g of the dihydrochloride of the title compound areobtained. M.p.: 220°-222° C.

EXAMPLE 71-(Indan-2-ylmethyl)-4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine##STR16##

The title compound was obtained in the same manner as the product ofExample 6, but with the use in Step 1 of4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine (Preparation 1)instead of 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine. Thehydrochloride of the title compound, obtained by the slow addition of anethereal hydrogen chloride solution to the base dissolved in ether,melts at 201°-204° C.

EXAMPLE 8 4-2-(Benzocyclohept-1-en-1-yl)ethyl!-1-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine##STR17##

Obtained in the same manner as the product of Example 6 but with the usein Step 1 of 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine insteadof 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine on the one hand, and2-(benzocyclohept-1-en-1-yl)acetic acid instead of indan-2-ylcarboxylicacid on the other hand.

The fumarate of the title compound melts at 207°-209° C. afterrecrystallisation from ethanol.

EXAMPLE 9 1-2-(Benzocyclobutan-1-yl)ethyl!-4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine##STR18## Step 1. "Amide"

Identical to Step 1 of Example 6 but using benzocyclobutan-1-ylaceticacid instead of indan-2-ylcarboxylic acid.

Step 2. Title compound

7.92 ml (79.2 mmol) of borane-dimethyl sulphide are added dropwise to7.9 mmol of the amide obtained above in 150 ml of anhydrous THF. Thewhole is heated at reflux for 6 hours. After returning to roomtemperature, the mixture is decomposed by pouring in dropwise 16 ml ofmethanol and then heating at reflux for 3 hours. After evaporation ofthe solvents an oil is obtained that corresponds to the title compound(yield=93%). The hydrochloride melts at 200°-204° C.

EXAMPLE 10 1-3-(Benzocyclobutan-1-yl)propyl!-4-(2,3dihydrobenzo-1,4-dioxin-6-yl)piperazine##STR19##

Prepared in the same manner as the title compound of Example 9 but usingthe method of operation of Step 1 of Example 6, in whichindan-2-ylcarboxylic acid has been replaced by3-(benzocyclobutan-1-yl)propionic acid, to prepare the amide(yield=79%). The dihydrochloride melts at 196°-199° C.

EXAMPLE 114-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-1-(indan-2-ylmethyl)piperidine##STR20## Step 1. "Amide"

Identical to Step 1 of Example 6 but using4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperidine (Preparation 2) insteadof 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine. After flashchromatography on silica with an eluant composed of the mixture CH₂ Cl₂/CH₃ COOC₂ H₅ : 95/5, the expected amide is obtained in a yield of 61%.

Step 2. Title compound

Identical to Step 2 of Example 9. The dihydrochloride of the titlecompound melts at 218°-220° C. (yield=42%).

EXAMPLE 12 1-(2,3-Dihydro-5-methoxybenzofuran-6-yl)-4-2-(1,2,3,4-tetrahydronaphthalen-1-yl)ethyl!piperazine ##STR21##

Prepared as described in Example 9, starting from1,2,3,4-tetrahydronaphthalen-1-ylacetic acid and4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of thetitle compound melts at 219°-220° C. after recrystallisation fromethanol.

EXAMPLE 13 1-(2,3-Dihydro-5-ethoxybenzofuran-6-yl)-4-2-(indan-2-yl)methyl!piperazine ##STR22##

Prepared as described in Example 9, starting from4-(2,3-dihydro-5-ethoxybenzofuran-6-yl)piperazine (Preparation 4). Thefumarate of the title compound melts at 183°-185° C. (ethanol).

EXAMPLE 14 1-3-(Benzocyclobutan-1-yl)propyl!-4-(benzo-1,5-dioxepin-7-yl)piperazine##STR23##

Prepared as described in Example 9, starting from3-(benzocyclobutan-1-yl)propionic acid and4-(benzo-1,5-dioxepin-7-yl)piperazine. The fumarate of the titlecompound melts at 168°-170° C. (ethanol).

EXAMPLE 15 4-(Benzo-1,5-dioxepin-7-yl)-1- (indan-2-yl)methyl!piperazine##STR24##

Prepared as described in Example 9, starting from4-(benzo-1,5-dioxepin-7-yl)piperazine. The hemi-fumarate of the titlecompound melts at 179°-181° C. (ethanol).

EXAMPLE 16 4- (2,3-Dihydrobenzo-1,4-dioxin-6-yl)methyl!-1-(indan-2-yl)methyl!piperazine ##STR25##

Prepared as described in Example 9, starting from 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)methyl!piperazine. The difumarate ofthe title compound melts at 217°-220° C. (ethanol).

EXAMPLE 17 4-(2,3-Dihydro-5-methoxybenzofuran-6-yl)!-1-(4,5,6,7-tetrahydrobenzob!thien-5-yl)methyl!piperazine ##STR26##

Prepared as described in Example 9, starting from4,5,6,7-tetrahydrobenzo b!thien-5-ylcarboxylic acid and4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of thetitle compound metls at 198°-200° C. (ethanol).

EXAMPLE 18 1-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-4-2-(naphth-1-yl)ethyl!piperazine ##STR27##

Prepared as described in Example 9, starting from naphth-1-ylaceticacid. The dihydrochloride of the title compound melts at 223°-232° C.(methanol).

EXAMPLE 19 1- (Cyclopentab!thien-5-yl)methyl!-4-(2,3dihydro-5-methoxybenzofuran-6-yl)piperazine##STR28##

Prepared as described in Example 9, starting from (cyclopentab!thien-5-yl)carboxylic acid (Preparation 8) and4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of thetitle compound melts at 186°-190° C. (ethanol).

EXAMPLE 20 1- (Cyclopentac!thien-5-yl)methyl!-4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine##STR29##

Prepared as described in Example 9, starting from (cyclopentac!thien-5-yl)carboxylic acid (Preparation 7) and4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The title compoundmelts at 156°-158° C.

EXAMPLE 21 4-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-1-2-(naphth-1-yl)ethyl!piperidine ##STR30##

Prepared as described in Example 11 but with the use in Step 1 ofnaphth-1-ylacetic acid instead of indan-2-ylcarboxylic acid. Thehydrochloride of the title compound melts at 220°-223° C. (methylcyanide).

EXAMPLE 22 1-(Acenaphthen-1-yl)methyl!-4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine##STR31##

Prepared as described in Example 9, starting fromacenaphthen-1-ylcarboxylic acid and4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of thetitle compound melts at 226°-228° C. (ethanol).

EXAMPLE 23 4-(2,3-Dihydro-7-methoxybenzo-1,4-dioxin-6-yl)-1-(indan-2-yl)methyl!piperazine ##STR32##

Prepared as described in Example 9, starting from4-(2,3-dihydro-7-methoxybenzo-1,4-dioxin-6-yl)piperazine (Preparation5). The fumarate of the title compound melts at 176°-178° C. (ethanol).

EXAMPLE 24 4-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-1-(1,2,3,4-tetrahydronaphth-2-yl)methyl!piperazine ##STR33##

Prepared as described in Example 9, starting from 1,2,3,4tetrahydronaphth-2-ylcarboxylic acid. The hydrochloride of the titlecompound melts at 226°-229° C. (methanol).

EXAMPLE 25 4-(2,3-Dihydro-5-methoxybenzofuran-6-yl)-4-(1,2,3,4-tetrahydronaphth-2-yl)methyl!piperazine ##STR34##

Prepared as described in Example 9, starting from1,2,3,4-tetrahydronaphth-2-ylcarboxylic acid and4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of thetitle compound melts at 219°-221° C. (ethanol).

EXAMPLE 261-(Acenaphthen-1-ylmethyl)-4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)piperazine##STR35##

Prepared as described in Example 9, starting fromacenaphthen-1-ylcarboxylic acid. The hydrochloride of the title compoundmelts at 192°-196° C. (ether).

EXAMPLE 27 1-(Indan-2-yl)methyl!-4-(8-methoxybenzo-1,5-dioxepin-7-yl)piperazine##STR36##

Prepared as described in Example 9, starting from4-(8-methoxybenzo-1,5-dioxepin-7-yl)-piperazine (Preparation 6). Thetitle compound melts at 120°-122° C. (ethanol).

EXAMPLE 28 4-(2,3-Dihydrobenzofuran-5-yl)-1-(indan-2-ylmethyl)piperazine##STR37##

Prepared as described in Example 9, starting from4-(2,3-dihydrobenzofuran-5-yl)-piperazine. The fumarate of the titlecompound melts at 180°-182° C. (ethanol).

EXAMPLE 294-(2,3-Dihydro-5-methoxybenzofuran-6-yl)-1-(indan-1-ylmethyl)piperazine##STR38##

Prepared as described in Example 9, starting from indan-1-ylcarboxylicacid and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. Thefumarate of the title compound melts at 195°-197° C. (ethanol).

EXAMPLE 30 4-(2,3-Dihydrobenzofuran-6-yl)-1-(indan-2-ylmethyl)piperazine##STR39##

Prepared as described in Example 9, starting from4-(2,3-dihydrobenzofuran-6-yl)-piperazine. The hemi-fumarate of thetitle compound melts at 171°-173° C. (ethanol).

EXAMPLE 31 4-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-1-(indan-2-yl)methyl!-1,2,3,6-tetrahydropyridine ##STR40## Step 1: "Amide"

Identical to Step 1 of Example 6, but using4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1,2,3,6-tetrahydropyridine(Preparation 3) instead of4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-piperazine.

Step 2: Title compound

4.4 ml (15.8 mmol) of Red-Al® 3.5M in toluene, are poured dropwise intoa solution of 1.9 g (5.2 mmol) of the amide prepared above in 60 ml oftoluene. The whole is heated for 2 hours at 50° C. and then stirredovernight at room temperature. The whole is then cooled with an ice bathand hydrolysed in succession with 2.2 ml of ethanol and 2.6 ml of water.The aluminium salts are filtered off and the filtrate is evaporated todryness. 1.4 g of an oil is obtained which is purified by flashchromatography.

The fumarate of the title compound melts at 160°-167° C. (ethanol).

Yield: 25%

EXAMPLE 32 4-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-1-2-(naphth-1-yl)ethyl!-1,2,3,6-tetrahydropyridine ##STR41##

Prepared as described in Example 28, but with the use in Step 1 ofnaphth-1-ylacetic acid instead of indan-1-ylcarboxylic acid. Thefumarate of the title compound melts at 170°-180° C. (ethanol).

EXAMPLE 33 4-(2,3-Dihydro-5-methoxybenzofuran-6-yl)-1-2-(1,2-dihydronaphthalen-3-yl)methyl!-piperazine ##STR42##

Prepared as described in Example 31, but in Step 1 using1,2-dihydronaphthalen-3-ylcarboxylic acid and4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of thetitle compound melts at 180°-184° C. (ethanol).

EXAMPLE 34 1-(Indan-2-ylmethyl)-4-(5-methoxybenzofuran-6-yl)piperazine##STR43##

Prepared as described in Example 31, but in Step 1 using4-(5-methoxybenzofuran-6-yl)piperazine. The fumarate of the titlecompound melts at 188°-192° C. (ethanol).

EXAMPLE 35 4-(Benzofuran-6-yl)-1-(indan-2-ylmethyl)piperazine ##STR44##

Prepared as described in Example 31 but in Step 1 using4-(benzofuran-6-yl)piperazine. The difumarate of the title compoundmelts at 168°-170° C. (ethanol).

Preparation of new starting materials

Preparation 1 4-(2,3-Dihydro-5-methoxybenzofuran-6-yl)piperazine

Step 1. 2,3-Dihydro-5-methoxy-6-nitrobenzofuran

15 g (100 mmol) of 2,3-dihydro-5-methoxybenzofuran dissolved in 15 ml ofglacial acetic acid are added dropwise at 0° C., over a period of 15minutes, to 18.7 ml of fuming nitric acid in 37.5 ml of water. The wholeis stirred for 1 hour at 0° C. and then for 1 hour 30 minutes at roomtemperature. The reaction mixture is poured into 125 ml of water, andthe resulting solid is filtered and washed abundantly with water. Afterdrying, 16.9 g of the expected product are obtained (yield=87%).M.p.=108°-109° C.

Step 2. 6-Amino-2,3-dihydro-5-methoxybenzofuran

7.1 g (36.4 mmol) of the compound obtained in the preceding Step in 100ml of methanol containing 100 mg of platinium oxide are hydrogenated atroom temperature and ordinary pressure for 3 hours. After filtering offthe catalyst and evaporating off the solvent, 5.85 g of the expectedamine are obtained in the form of an oil (yield=97%).

Step 3. Title compound

5.75 g (34.8 mmol) of the amine obtained above, 6.2 g (34.8 mmol) ofbis(2-chloroethyl)amine hydrochloride and 4.81 g (34.8 mmol) ofpotassium carbonate dissolved in 90 ml of chlorobenzene are heated atreflux for 22 hours. The whole is poured into water and thechlorobenzene is decanted off. The aqueous phase is rendered basic with12 ml of concentrated sodium hydroxide solution and extracted twice with250 ml of ethyl acetate each time. The organic phases are washed with250 ml of a saturated NaCl solution. After drying, 5.95 g of theexpected product, purified in the form of its hydrochloride, areobtained. M.p.>260° C.

Preparation 2 4-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)piperidine

Step 1. Magesium compound of 6-bromo-2,3-dihydrobenzo-1,4-dioxin

10 g (46 mmol) of 6-bromo-2,3-dihydrobenzo-1,4-dioxin dissolved in 100ml of THF are added rapidly to a suspension of 1.1 g (0.046 g.atom) ofmagnesium in 20 ml of THF. The reaction is started by heating in thepresence of an iodine crystal and a few drops of methyl iodide. When theaddition is complete (approximately 15 minutes), the whole is heated atreflux for 1 hour. A perfectly clear solution is obtained.

Step 2. 1-Benzyl4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-4-hydroxypiperidine

6.9 g (37 mmol) of N-benzylpiperid-4-one dissolved in 80 ml of THF areadded at 0° C. to the solution of Grignard reagent obtained above. Whenthe addition is complete, the whole is stirred at room temperature for 2hours, then hydrolysed with a saturated NH₄ Cl solution. The whole isconcentrated to dryness and then the residue is taken up in ether andextracted with 1N HCl. The acidic phase is rendered basic with N sodiumhydroxide solution and then extracted with ether. That ethereal phase isdried and then evaporated to dryness. 8 g of the expected product(yield=67%) are obtained. M.p.=154°-156° C.

Step 3.1-Benzyl-4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1,2,3,6-tetrahydropyridine

4 g (12.3 mmol) of the product obtained in Step 2 are added to 50 ml oftrifluoroacetic acid. The whole is heated for 30 minutes at 60° C.,cooled and neutralised with 35% sodium hydroxide solution. Extraction iscarried out with ether and the extract is washed with water, dried overMgSO₄, filtered and evaporated to dryness. The residue obtained ispurified by chromatography on silica (eluant: CH₂ Cl₂ /CH₃ OH: 95/5).1.5 g of the desired product are obtained in the form of an oil(yield=40%).

Step 4. Title compound

3.2 g (10.4 mmol) of the product obtained in Step 3 are dissolved in 150ml of ethanol. 1.5 g of 20% Pd(OH)₂ on carbon are added and the whole ishydrogenated at room temperature for 24 hours under a pressure of 4×10⁵Pa. The catalyst is filtered off and the filtrate is evaporated todryness. 1.7 g of the expected product are obtained in the form of anoil (yield=77%).

Preparation 34-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)1,2,3,6-tetrahydropyridine

2 g (6.5 mmol) of the compound obtained in Step 3 of Preparation 2 aredissolved in 30 ml of 1,2-dichloroethane. 1.2 ml (13 mmol) of ethylchloroformate are added and then the whole is heated at reflux for 2hours, cooled and evaporated to dryness. The residue is taken up in 30ml of ethanol and 0.7 g (13 mmol) of potassium hydroxide and then heatedat reflux for one night. The whole is cooled, 20 ml of water and afurther 1.05 g (19.5 mmol) of potassium hydroxide are added, and thewhole is heated at reflux again for two days. After evaporation of theethanol, the mixture is diluted with water and extracted with ethylacetate, dried over MgSO₄, filtered and evaporated to dryness to yield1.4 g of the title compound (yield: 100%).

Preparation 4 4-(2,3-Dihydro-5-ethoxybenzofuran-6-yl)piperazine

Obtained in the same manner as the product of Preparation 1 but with thereplacement in Step 1 of 2,3-dihydro-5-methoxybenzofuran with2,3-dihydro-5-ethoxybenzofuran. Maroon solid (m.p.=68°-69° C.)

Preparation 5 4-(2,3-Dihydro-7-methoxybenzo-1,4-dioxin-6-yl)piperazine

Obtained in the same manner as the product of Preparation 1 but with thereplacement in Step 1 of 2,3-dihydro-5-methoxybenzofuran with2,3-dihydro-7-methoxybenzo-1,4-dioxin. The hydrochloride of the titlecompound melts at: 180°-182° C.

Preparation 6 4-(8-Methoxybenzo-1,5-dioxepin-7-yl)piperazine

Obtained in the same manner as the product of Preparation 1 but with thereplacement in Step 1 of 2,3-dihydro-5-methoxybenzofuran with8-methoxybenzo-1,5-dioxepin. The hydrochloride of the title compoundmelts at 187°-189° C.

Preparation 7 Cyclopenta c!thien-5-ylcarboxylic acid

Step 1: Cyclopenta c!thiophene-5,5-dicarboxylic acid diethyl ester

At room temperature, 4.5 g (15.0 mmol) of 3,4-bis-(bromomethyl)thiophene(the synthesis of which is described in J. Prakt. Chem. 1972, 314(2),334-352), 2.3 ml (15.0 mmol) of diethyl malonate, 4.3 g (31.0 mmol) ofpotassium carbonate and 75 ml of methyl ethyl ketone are mixed together.The whole is heated at reflux for 20 hours, then evaporated to dryness,taken up in 200 ml of dichloromethane and washed twice with 50 ml ofwater each time. After drying over magnesium sulphate, then evaporation,the residue is chromatographed on silica (eluant:dichloromethane) toyield 1.8 g of the desired compound (yield: 45%).

Step 2: Cyclopenta c!thiophene-5,5-dicarboxylic acid

A solution of 2.2 g (38.8 mmol) of potassium hydroxide in 2.2 ml ofwater is added in one go to 2.6 g (9.7 mmol) of the above compound in 5ml of ethanol. The whole is heated at reflux for 6 hours and thenevaporated to dryness. The residue is taken up in 50 ml of Nhydrochloric acid and extracted 3 times with 80 ml of ether each time.The combined ethereal phases are dried over magnesium sulphate and thenconcentrated to yield 1.85 g of the desired compound (yield: 88%).

Step 3: Cyclopenta c!thien-5-ylcarboxylic acid

1.8 g (8.5 mmol) of the above compound in 8.5 ml ofN,N-dimethylacetamide is heated at reflux for 1 hour. The whole is thenevaporated to dryness and subsequently taken up in 100 ml of ether andwashed 4 times with 50 ml of water each time. After drying overmagnesium sulphate, then evaporation, 1.32 g of the desired compound areobtained (yield: 94%).

Preparation 8 Cyclopenta b!thien-5-ylcarboxylic acid

Step 1: Methyl 3-(thien-3-yl)-3-oxopropanoate

24 g (0.6 mmol) of sodium hydride (60%) are added in portions at 0° C.,over a period of 10 minutes, to 25.2 g (0.2 mmol) of 3-acetylthiophenein 600 ml of dimethyl carbonate, and then the whole is heated at refluxfor 30 minutes, allowed to cool and poured into 1 liter of a water/icemixture containing 53 ml of acetic acid. Extraction is carried out 3times with 250 ml of ether each time. The combined organic phases aredried over magnesium sulphate. After evaporation, the residue ischromatographed on silica (eluant:dichloromethane) to yield 17 g of thedesired compound (yield: 46%).

Step 2: 4-Oxocyclopenta b!thien-5-ylcarboxylic acid methyl ester

At room temperature, 4.9 g (26.6 mmol) of the above keto ester are addedto 7.8 g (58.5 mmol) of aluminium chloride in 75 ml of nitromethane andthe whole is then stirred for 15 minutes. 2.9 ml (31.9 mmol) of2-methoxyacetyl chloride in 25 ml of nitromethane are then addeddropwise over a period of 10 minutes, and the whole is heated at 80° C.for 3 hours, allowed to cool and poured into 100 ml of an aqueous 10%oxalic acid solution, then extracted 3 times with 100 ml of ether eachtime. The combined ethereal phases are washed twice with 150 ml of asaturated aqueous sodium hydrogen carbonate solution each time, driedover magnesium sulphate and concentrated, the residue beingchromatographed on silica to yield 2.85 g of the desired compound(yield: 55%).

Step 3: Cyclopenta b!thien-5-ylcarboxylic acid methyl ester

In a mortar, 7 g (107.2 atom-gram) of zinc are intimately mixed with0.78 g (2.9 mmol) of mereuric chloride, then the whole is stirredvigorously for 10 minutes in 10 ml of water containing 0.3 ml ofconcentrated hydrochloric acid. The aqueous phase is decanted off andthen 6 ml of water, 12 ml of concentrated hydrochloric acid acid and 2.8g (14.3 mmol) of the above compound in 15 ml of toluene are added insuccession. The whole is heated at reflux for 18 hours, then allowed tocool, and the amalgam is separated off and extracted twice with 20 ml ofether each time. The combined organic phases are washed twice with 20 mlof an aqueous 10% sodium carbonate solution each time, dried overmagnesium sulphate and concentrated, the residue being chromatographedon silica (eluant:dichloromethane+2% ethyl acetate) to yield 1.15 g ofthe desired compound (yield: 44%).

Step 4: Cyclopenta b!thien-5-ylcarboxylic acid

1.05 g (5.8 mmol) of the above compound and 3.5 ml (7 mmol) of 2N sodiumhydroxide solution in 6 ml of methanol are stirred at room temperaturefor 24 hours, then evaporated to dryness, taken up in 50 ml of water,washed twice with 25 ml of ether each time, acidified with Nhydrochloric acid and extracted 3 times with 40 ml of ether each time.The combined ethereal phases are dried over magnesium sulphate andconcentrated to yield 0.86 g of the desired compound (yield: 88%)

EXAMPLE 30 Pharmacological study

In vitro Determination of the affinitiy for human D₄ receptors

Membranes prepared from CHO cells transfected with human D₄ receptorwere bought from Receptor Biology Inc. (MD, U.S.A.). The membranes areincubated in triplicate with 30 μg of membrane protein, 0.5 mmol of ³ H!spiperone and cold ligand in a final volume of 1 ml, for 60 minutes at25° C. The incubation buffer contains 50 mM Tris-HCl (pH 7.4), 120 mMNaCl, 5 mM KCl, 5 mM MgCl₂ and 1 mM EDTA. After incubation, theincubation medium is filtered across WHATMAN GF/B filters impregnatedwith 0.1% polyethyleneimine, and washed three times with 2 ml of cooledbuffer each time. The radioactivity retained on the filters isdetermined by liquid scintillation counting. The binding isotherms areanalysed by an informed non-linear regression method for determiningIC₅₀ values. They are converted into the inhibition constant (K_(i)) bymeans of the Cheng-Prusoff equation: ##EQU1## in which L is theconcentration of free ³ H! spiperone and Kd is the ³ H! spiperonedissociation constant of the human D₄ receptor (70 pM).

The products of the invention have K_(i) values for the D₄ receptor ofless than 5×10⁻⁸ M.

Determination of the affinity for human D₂ receptors

The procedure used here has already been described in detail in theliterature. CHO cells are transfected in a stable manner with cDNAcoding for human D₂ receptor and, for the binding studies, the membranesare incubated with 0.1 nM ¹²⁵ I!-iodosulpiride and the specific bindingis greater than 90%. The IC₅₀ and K_(i) values are determined andcalculated as above. The products of the invention have K_(i) values forthe D₂ receptor greater than 10⁻⁶ M.

In vivo

a) Pharmacological models

Male Wistar rats (Iffa Credo, Illskirchen France) weighing 250 to 280 gare kept in a 12h/12h light/darkness cycle (light switched on at 7.30a.m.). They have free access to water and food; the laboratorytemperature is 21°±1° C. and the humidity is 60±5%.

Dopamine turnover: The effect of the products of the invention and thereference product on dopamine turnover is determined after subcutaneousinjection. After a period of 30 minutes, the rats are decapitated andthe brain is dissected in order to extract the striatum, the nucleusaccumbens, the frontal cortex and the olfactory tubercles. The tissuesare homogenised in 500 μl of HClO₄ 0.1M containing 0.5% Na₂ S₂ O₅ and0.5% EDTA Na₂ and centrifuged at 15,000 g for 15 minutes at 4° C. Thesupernatants are diluted in the mobile phase and injected into an HPLCcolumn (Hypersil ODS 5 μm, C18, 150×4.6 mm, Thermo Separation Products,Les Ulis, France) thermostatically controlled at 25° C. The HPLC mobilephase is composed of 100 mM KH₂ PO₄, 0.1 mM EDTA, 0.5 mM sodiumoctylsulphonate and 5% methanol adjusted to pH 3.15 with H₃ PO₄.

The mobile phase is injected with a BECKMAN 116 pump and at a flow rateof 1 ml/min. The electrochemical detection is carded out by a WatersM460 detector of which the potential of the working electrode is 850 mVrelative to an Ag/AgCl reference. The quantities of dopamine and ofdihydroxyphenylacetic acid (DOPAC), a metabolite of dopamine, areexpressed in relation to the amount of proteins contained in the removedcerebral structure. Bovine serum albumin (Sigma Chemical Co, St-Louis,Mo.) is used as the reference. The DOPAC/dopamine ratio is calculatedand is used as the turnover index. For each experiment the ratio betweenthe average amount (±SD) of dopamine and of DOPAC is determined bycomparison with the values obtained in the case of the amimals treatedwith the carrier (100%).

The activity of the products of the invention and of the referenceproduct is expressed in relation to that control value and is reportedby way of example in the following Table.

    __________________________________________________________________________    DA: DOPAC ratio (% ± SD)                                                         Dose Frontal                                                                              Nucleus                                                                              Olfactory                                            Products                                                                            (mg/kg)                                                                            cortex accumbens                                                                            tubercles                                                                           Striatum                                       __________________________________________________________________________    Carrier                                                                             --   100.0 ± 18.2                                                                      100.0 ± 7.8                                                                       100.0 ± 7.7                                                                      100.0 ± 2.2                                 Haloperidol                                                                         0.63                                                                             s.c                                                                             232.1* ± 8.3                                                                      358.5* ± 15.6                                                                     298.5* ± 8.9                                                                     371.5* ± 17.8                               Example 6                                                                           40.0                                                                             s.c                                                                             153.0* ± 10.4                                                                     147.1* ± 9.5                                                                      125.2* ± 1.6                                                                     139.3* ± 8.4                                      160.0                                                                            p.o                                                                             167.2* ± 16.1                                                                     195.4* ± 18.3                                                                     155.2* ± 8.8                                                                     197.1* ± 15.3                               __________________________________________________________________________     N ≧ 5 per value.                                                       *p ≦ 0.05 vs carrier                                              

Those results show that, like haloperidol, the compounds of theinvention have a significant effect on dopaminergic transmission in eachof the regions studied, indicating a good activity in vivo and a goodbioavailability by the oral route.

Dialysis: Rats are anaesthetised with pentobarbital (60 mg/kg i.p.).They are placed in a Kopf stereotaxic device and cannula guides(intracerebral guides, Carnegie Medicine, Stockholm, Sweden) areimplanted either in the striatum and the contralateral nucleus accumbensor in the cingulate frontal cortex in accordance with the respectivecoordinates described as follows in the Paxinos and Watson atlas (1982):nucleus accumbens (CMA/12, AP:+1.6, L:±1.4, DV:-5.7); striatum (CMA/12,AP:+0.5, L:±2.8, DV:-3) and cingulate frontal cortex (CMA/11, AP:+2.2,L:±0.6, DV:-0.2). The rats are placed in separate cages and are not usedin dialysis until 5 days later. On the day of the dialysis, CMA/12probes made of polycarbonate (striatum: 3 mm long, 0.5 mm externaldiameter, nucleus accumbens: 2 mm long, 0.5 mm external diameter) andCMA/11 probes made of cuprophan (cingulate frontal cortex: 4 mm long,0.24 mm external diameter) are slowly lowered and held in position.Those probes are perfused at a flow rate of 1 ml/min with a solution of147.2 mM NaCl, 4 mM KCl and 2.3 mM CaCl₂ adjusted to pH 7.3 with aphosphate buffer (0.1M). Two hours after implantation, samples arecollected every 20 minutes for 4 hours. Three base samples are takenbefore administration of the products to be tested. The rats are left intheir individual cages for the whole of the experiment. When theexperiment is finished, the rats are decapitated and the brain isremoved and frozen in cold isopentane. Sections of a thickness of 100 μmare cut and coloured with cresyl violet, which allows verification ofthe location of the probes.

The simultaneous quantification of dopamine, norepinephrine andserotonin is carried out as follows: 20 μl of dialysis samples arediluted with 20 gl of mobile phase (NaH₂ PO₄ : 75 mM, EDTA: 20 μM,sodium dodecanesulphonate: 1 mM, methanol: 17.5%, triethylamine: 0.01%,pH: 5.70) and 33 μl are analysed by HPLC with a reverse phase column(Hypersil ODS 5 μm, C18, 150×4.6 mm, Thenno Separation Products, lesUlis, France), which is thermostatically controlled at 45° C., andquantified by means of a coulometric detector (ESA 5014, Coulochem II,Bedford, Mass., U.S.A.). The potential of the first electrode of thedetector is set at -90 mV (reduction) and the second at +280 mV(oxidation). The mobile phase is injected with a Beckman 116 pump at aflow rate of 2 ml/min. The sensitivity limits for dopamine,norepinephrine and serotonin are 0.55 fmole per sample. All the productsof the invention and the reference substance are injected by thesubcutaneous route in a volume of 1.0 ml/kg. The products are dissolvedin distilled water to which a few drops of lactic acid have been addedif necessary. The quantities of neurotransmitters are expressed as afunction of the average of the 3 base values. A variance analysis, withthe time factor as repeated measurement, followed by a Newman-Keuls test(p<0.05) is employed for the statistical evaluation of the effects ofthe products. The activity of the products of the invention and of thereference product is expressed by the percentage variation of thequantity of neurotransmitter after administration of the productscompared with the base value (=100%).

By way of example, the changes recorded in respect of the quantity ofdopamine are given in the Table below.

    ______________________________________                                        Average ± SD in %                                                                  Dose                 Nucleus                                          Products                                                                              (mg/kg)   Frontal cortex                                                                           accumbens                                                                             Striatum                                 ______________________________________                                        Carrier --        100.0 ± 14.3                                                                          100.0 ± 8.9                                                                        100.0 ± 5.6                           Haloperidol                                                                           0.63 s.c. 148* ± 9                                                                              133* ± 7                                                                           129* ± 7                              Example 6                                                                             40.0 s.c. 201* ± 12                                                                             103* ± 6                                                                           104* ± 8                              ______________________________________                                         N ≧ 5 per value * p ≦ 0.05 vs carrier                      

Those results show that, contrary to the reference product, the productsof the invention increase mesocortical dopaminergic transmission. Thateffect shows that the products of the invention enable more effectivecontrol of the deficient symptoms of schizophrenia and also haveanti-depressant and pro-mnesic propertieis.

b) Therapeutic models

1. Verticalisation induced by apomorphine (0.75 mg/kg, s.c.) in themouse

This test, described by Protais et al (Psychopharmacologie, 1976, 50,1-6) allows the evaluation of the dopaminergic antagonist activity ofpossible antipsychotic products. A mouse to which apomorphine has beenadministered and which has been placed in a cage comprising verticalbars, remains most of the time immobile at the top of the cage clingingby its 4 paws to the bars. That verticalisation behaviour is blocked ifa dopaminergic antagonist product has been administered before theapomorphine.

Test: After the subcutaneous (s.c.) administration of the product orsolvent (control group), the mouse is placed in a cylindrical barredcage (14 cm diam.×14 cm h) having vertical bars. Thirty minutes later,the animal receives the apomorphine dose (0.75 mg/kg, s.c.). The animalsare observed 10 and 20 minutes after the injection of apomorphine andare given a score 0 (4 paws on the ground), a score 1 (mouse uprightwith the two front paws on the bars) or a score 2 (mouse clinging by its4 paws to the bars) each time a measurement is taken. Theverticalisation score used for the results is from 0 to 4 (the sum oftwo measurements). Each experimental group comprises at least 5 animals.

Statistical analysis: The effect of the product on verticalisation isevaluated by comparing the scores obtained for each group that has beenadministered a dose of product with those obtained for the control group(solvent) using a Mann and Whitney U test, with a probability p<0.05.The ID₅₀ is that dose of product which reduces by half the average ofthe verticalisation scores compared with that of the control group.

Results: As an example, and in order to illustrate the effect of theproducts of the invention, the ID₅₀ for the compound of Example 6 is3.88 mg/kg by the subcutaneous route.

2. Test of aggressiveness in isolated mice

This test allows the evaluation of the intraspecies anti-aggressiveactivity of a product in mice that have been kept in isolation forseveral months.

Animals: The test uses male CD mice (Charles River) weighing from 22 to25 g when they arrive at the animal house. On their arrival, the animalsare isolated in individual cages made of opaque black polycarbonate(23×14×13 cm) with a grill lid, and are housed for a prolonged period(approximately 6 months) in the experimentation room.

Selection of pairs of mice: The selection of aggressive pairs of micethat will be used chronically in the study commences after the animalshave been isolated for one month. Once or twice per week a mouse fromanother cage (intruder) is placed in the cage of a (resident) mouse andthe two animals are observed to see if they attack one another(sniffing, pursuing, nipping, biting) during that trial. At the end ofthe trial (maximum duration 10 minutes), each mouse is isolated again inits own cage. If attacks have occurred, the same pair of mice will betested again in the next trial; if there have been no attacks, eachmouse of that pair will be placed in the presence of another mouse inthe subsequent trial. Thus, in the course of successive trials carriedout at a rate of 1 or 2 per week, definitive pairs of mice that will beused for the experiments are selected. The selection of the pairs isbased on the stability of the combative nature of the animals from onetrial to the next, the shortness of the latent period of the firstattack and the frequency and duration of the attacks. With the pairsselected in that manner, those parameters are checked each week by arapid trial, without treatment, two days before the Test day.

Test: The test takes place once a week. Thirty minutes before beingplaced together, the two mice of the pair each receive the sametreatment (product or solvent) and remain isolated in their respectivecages. At TO min., the intruder mouse is introduced into the cage of theresident mouse for a period of 3 minutes. The latent period (in seconds)of the first attack and the number and total duration (in seconds) ofthe attacks are recorded. A possible reversal of the dominance of onemouse in relation to the other is also noted (in general, the residentmouse is the dominant mouse).

At the end of the test, the intruder mouse returns to its cage; theanimals remain in isolation until the next rapid trial and test thefollowing week.

Statistical analysis: The effects of a product on aggressiveness areevaluated by comparing the number and the duration of the attacks by thepairs of mice that have received the product (treated groups) with thoseobtained with the pairs that have received the solvent (control group)by using a variance analysis (ANOVA) followed by a Dunnett's test, withthe probability p<0.05.

The ID₅₀ of the number or the duration of the attacks is that dose ofthe product which reduces by half the average of each of those valuescompared with those obtained respectively in the control group.

Results: As an example, and in order to illustrate the activity of theproducts of the invention, the ID₅₀ for the compound of Example 6 is0.99 mg/kg by the subcutaneous route.

3. Induction of catalepsy in the rat

The prolonged administration of "typical" neuroleptics or antipsychotics(haloperidol, chlorpromazine) to schizophrenia patients often bringsabout the appearance of undesirable extrapyramidal symptoms (EPS) of theParkinson's type, in particular an immobility phenomenon (Davis et al.,1983). By way of contrast, "atypical" antipsychotics (clozapine) causefew extrapyramidal symptoms.

The acute administration of "typical" antipsychotics to an animalinduces catalepsy, that is to say the maintenance of the animal in anoften abnormal posture which has been imposed upon it by theexperimenter (Waldmeier, 1979). The evaluation of the cataleptogenicproperties of a product in the rat thus makes it possible to knowwhether that product, administered to man, will or will not risk causingan extrapyramidal-type syndrome.

Test: The animals are placed in individual cages and food is withdrawnthe day before the test but water taken as desired. The catalepsy testcomprises placing each rear paw of the animal on the front paw of thesame side and measuring the time (seconds) that the animal remains inthat "crossed paws" position (maximum 30 seconds). Each animal issubjected to 3 successive tests (one every two minutes), the animalbeing removed from its cage and placed on the work surface. Those testsare carded out 1 hour after the subcutaneous injection or oraladministration of the product or its solvent. The average value of 3tests represents the duration of the catalepsy (seconds) for eachanimal. There are 5 or 6 rats per experimental group.

Statistical analysis: The effect of the product on the duration of thecatalepsy is evaluated by an ANOVA, followed by a Dunnett's test, withthe probability p<0.05.

The ED₅₀ of cataleptsy induction is that dose which causes a catalepsyof a duration of 50% compared with the maximum value of 30 seconds(corrected by the value of the solvent control group).

Results: As an example and in order to illustrate the absence of acataleptogenic effect of the compounds of the invention, the compound ofExample 6 has an ED₅₀ greater than 80 mg/kg by the subcutaneous route.By comparison, haloperidol, the reference antipsychotic, has an ED₅₀ of0.146 mg/kg by the same route. This result shows the great value of aselective blockade of D₄ receptors compared with D₂ receptors inavoiding the extrapyramidal-type side effects encountered withantipsychotics that have a mechanism of action based, inter alia, on ablockade of D₂ receptors.

We claim:
 1. A compound selected from those of formula I: ##STR45##wherein A-B is selected from the group consisting of: CH₂ --CH andCH═C,n is selected from the group consisting of zero and 1 to 6inclusive, D represents one of the following bicyclic systems: ##STR46##wherein: R₁ and R₂, which are identical or different, are each selectedfrom the group consisting of hydrogen, halogen, straight-chain andbranched alkyl and alkoxy each having 1 to 5 carbon atoms inclusive, andhydroxy; and E represents one of the following heterocycles: ##STR47##with the proviso that E does not represent: ##STR48## when D is##STR49## its racemic mixtures or racemates and optical isomers orenantiomers and salts thereof with a pharmaceutically acceptable acid.2. A new intermediate product selected from those compounds of formulaV: ##STR50## wherein A-B, D, and E are as defined in claim 1 and n' is 1to 6 inclusive.
 3. A method for treating a living animal body afflictedwith a condition associated with a dysfunction of the dopaminergicsystem, comprising the step of administering to the living animal bodyan amount of a compound of claim 1 which is effective for alleviation ofsaid condition.
 4. A pharmaceutical composition acting as D4 receptorligand and useful in the alleviation of a dopaminergic systemdysfunction, comprising as active ingredient at least one of thecompounds according to claim 1, together with one or more pharmaceuticalexcipients.
 5. A compound of claim 1 selected from the group consistingof 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1-(indan-2-ylmethyl)piperidineand its dihydrochloride.
 6. A compound of claim 1 selected from thegroup consisting of 4-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1-(indan-2-yl)methyl!-1,2,3,6-tetrahydropyridine and its fumarate.